The discovery of the hepcidin peptide and characterization of its gene, HAMP, has led to the revision of previous models for the regulation of iron homeostasis and the realization that the liver plays a key role in determining iron absorption from the gut and iron release from recycling and storage sites. In summary, the hepcidin model proposes that the rate of iron efflux into the plasma depends primarily on the plasma level of hepcidin; when iron levels are high the synthesis of hepcidin increases and the release of iron from enterocytes and macrophages is diminished. Conversely when iron stores drop, the synthesis of hepcidin is down-regulated and these cells release more iron. Hepcidin directly binds to ferroportin and decreases its functional activity by causing it to be internalized from the cell surface and degraded.
Hepcidin provides a unifying hypothesis to explain the behavior of iron in two diverse but common clinical conditions, the anemia of chronic disease and both HFE and non-HFE haemochromatosis. The pathophysiology of hepcidin has been sufficiently elucidated to offer promise of therapeutic intervention in both of these situations. Administering either hepcidin or an agonist could treat haemochromatosis, where the secretion of hepcidin is abnormally low.
The anemia of inflammation, commonly observed in patients with chronic infections, malignancy, trauma, and inflammatory disorders, is a well-known clinical entity. Until recently, little was understood about its pathogenesis. It now appears that the inflammatory cytokine IL-6 induces production of hepcidin, an iron-regulatory hormone that may be responsible for most or all of the features of this disorder. (Andrews N C. J Clin Invest. 2004 May 1; 113(9): 1251-1253). As such, down regulation of hepcidin in anemic patients will lead to a reduction in inflammation associated with such anemia.
Double-stranded RNA molecules (dsRNA) have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). WO 99/32619 (Fire et al.) discloses the use of a dsRNA of at least 25 nucleotides in length to inhibit the expression of genes in C. elegans. dsRNA has also been shown to degrade target RNA in other organisms, including plants (see, e.g., WO 99/53050, Waterhouse et al.; and WO 99/61631, Heifetz et al.), Drosophila (see, e.g., Yang, D., et al., Curr. Biol. (2000) 10:1191-1200), and mammals (see WO 00/44895, Limmer; and DE 101 00 586.5, Kreutzer et al.). This natural mechanism has now become the focus for the development of a new class of pharmaceutical agents for treating disorders that are caused by the aberrant or unwanted regulation of a gene.
The following publications disclose dsRNA (siRNA) targeting the HAMP gene and are herein incorporated by reference for all purposes: WO 2008/036933 (International application no. PCT/US2007/079212, filed Sep. 21, 2007); US 2009-0209478 (U.S. patent application Ser. No. 11/859,288, filed Sep. 21, 2007); US 2010-0204307 (U.S. patent application Ser. No. 12/757,497, filed Apr. 9, 2010); US 2011-0269823 (U.S. patent application Ser. No. 13/184,087, filed Jul. 15, 2011).